Persons infected with human immunodeficiency Virus (HIV) developed a severe form of transmissible immune deficiency. The immune defect results in opportunistic infecitons and malignancies. There are over 750,000 Americans with HIV infection and death from HIV infection occurs in greater that 95 percent of HIV infected individuals. Current treatments select for viral resistance which limits the clinical efficacy of current drugs. As yet, there is no therapeutic intervention which results in the elimination of infection by HIV. Consequently, there is not cure for HIV infection. Prevention of infection remains a major public health aim. Intervention efforts which would afford an increased level of safety for persons engaging sexual intercourse with high-risk individuals could substantially decrease the rate of new transmissions of HIV in the United States. Protegrins are a unique, new class of small peptide antibiotics with antiretroviral activity. They are stable to proteolytic cleavage and chemical denaturation, poorly immunogenic, and rapidly taken up by target cells. At 5 mug/mL, natural and synthetic protegrin completely inhibited de novo HIV infection with a primary clinical isolate (JR-CSF) in human peripheral blood lymphoblast cultures. Similar effects were seen in monocyte cultures using JR-FL. Protegrins inhibited infection if added before inoculation and up to two hours later. No effects were seen if added after 24 hours. There are significant structure/activity features as truncated versions of protegrins and related peptide antibiotics either had reduced or no effect. This application proposes to significantly expand our understanding of the biology of protegrins as anti-HIV prophylactic and therapeutic agents. We will evaluate a series of protegrin derivatives in order to optimize the activity of these agents. We will survey their activity against other retroviruses and will delineate the nature of the structure/activity relationships. Finally, we will identify the site in HIV replication where protegrins act and develop high volume screening assays to be used to identify newer and more active derivative peptides and peptidomimetics. The ultimate goal is to develop protegrins as a preventative agent for the transmission of HIV when used during intercourse and as a potential therapeutic agent for those already infected with HIV.